IN THE NAME OF GOD A 20 yrs. Young boy - PowerPoint Presentation

1. IN THE NAME OF GODA 20 yrs. Young boy known case of Histiocytosis Referred for Panhypopituitarism + Hands & feet bigness1Presentation By Dr. Ali Golshaian20th Tir 1401

2. Patients ID:20 yrs. Young man Born & live in Eslamshahr - TehranEducated until Class 11Working in Box making 2

3. Present Illness:He is referred by one of our colleagues due to: ↓Cortisol + 2nd Hypogonadism + Acromegaloid featureHis recent main problem (~ 1 y) compelling patient to refer to a doctor, is bigness of his feet & hands, also feet & ankle malalignment.He is known case of Histiocytosis from childhood.3

4. Past medical history: He is born at 1381.12.06His mother`s pregnancy (especially 1st trimester) coincided with Chemotherapy, Radiotherapy & Surgery due to Breast tumor.At under 2 yrs old, probably, polyuria has resulted in diagnosis of DI.After diagnosis until now, patient uses Spray DDAVP (1 puff / day)4

5. Past medical history: Document at 1383.12.09 (at 2 yrs Old):C.C: OK for COM surgeryHx of DIWt: 12 Kg Ht: 88 cmLeft dental abscess Both TM inflammation Dental falling – Maxilla 5

6. Past medical history: Document at 1384.02.19:Referring to Pediatric Oncologist due toPathology of Rt Middle Ear report:Histiocytosis 6

7. Past medical history: He received regular & programizied Chemotherapy (?) for ~ 3 yrs.At ~ 3 – 4 yrs old, patient manifested polyphagia & obesity.He became Obese more over than his same ages.About 7 yrs old, Second course of chemotherapy was begun with these manifestation: Inflammation in mandible + Dental instability + Cystic lesion in OPG (on base his oncologist documentation)7

8. Past medical history: MRI 1387.06.07Small lobulated (14*10 mm) nodule posterior to optic chiasma in suprasellar cistern (residual histiocytic mass ?) 8

9. Past medical history: At 1400.11:After over 10 yrs, He referred to doctor due to Bigness of his feet & hands & his feet malalignment.He was visited by an Endocrinologist and due to his appearance & delayed puberty some laboratory evaluation was done. >>> Panhypopituitarism was diagnosed & treatment was begun. During over 10 yrs before recent visiting, without any F/U: His stature among school times, seems be good and about mid range of Nl on base of his father speeches.9

10. Past medical history: At last, he was referred to this center:↓Cortisol + 2nd Hypogonadism + Acromegaloid feature10

11. Habitual History: Neg Social History : NegFamily History : Neg11

12. Drug History: Levothyroxine 600 μg / weekPrednisolone 5 mg / dayTestosterone 200 mg / 2 weeksSpray DDAVP 1 puff / day12

13. Review of Systems:Hand & Foot Bigness / No Gigantism / No Frontal bossing Dental problems Headache (-) Nausea & Vomiting (-) Visual problems (-)Weight changes (Now: Neg, Hx: +) Appetite changes (Now: Neg, Hx: +) Skin: Acanthosis nigricans (+)Cardiovascular: Nl, Palpitation (-) Respiratory: NlGastrointestinal: Nl, Musculoskeletal: Nl Neurological: Nl13

14. Physical Examination:GENERAL APPEARANCE: 20 yrs. old man with boyish face, awake and alertVital Sign: BP: 110/80 mmHgHeight: 176 cm Arm Span: 179 cmUpper: 87 cm Lower: 89 cmWeight: 101 kg BMI: 32.6 14

15. Physical Examination:Acromegaliod feature: Gigantism (-) / Hand & Foot Enlargement (+) / Frontal bossing (-) / Prominent Nose (-) / Ear Enlargement (-)Face: Scares beardDental problems: FallingsNeck: Acanthosis Nigricans Thorax, Heart, Lung: NlAbdomen : Nl - ObeseExtremities : Upper : Mild hands enlargement Lower Mild feet enlargementGenital: Testis V: 4 cc, SPL: 9 cm >>> G1 P1>215

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18. PROBLEM LIST 20 yrs. Young manknown case of Histiocytosis from childhood1st presentation: DI under 2 yrs old COM candidate for surgery + Left dental abscess (Maxilla) at 2 yrs oldNormal documented growth until 2 yrs old Regular & programizied Chemotherapy after Histiocytosis diagnosis Polyphagia & obesity, about 3-4 yrs oldRecurrent bone involvement (mandible + Dental instability) at 7 yrs oldAnother course of chemotherapy At 19 yrs old: Bigness of his feet & hands & his feet malalignment He was visited by a Endocrinologist >>> Panhypopituitarism18

19. 1400.11.161401.01.281401.03.09IGF146.4ng/ml (91-442)Growth Hormone1.8 nmol/l GH (60 min)0.45 nmol/l GH (120 min)0.07 nmol/l Cortisol 8 AM0.7 ng/ml (3.7-19.4)ACTH6.19 pg/ml (7-69)TSH4.090.051.2T42.846.317.2LH0.31 mIu/ml (0.8-6)0.99 mIu/ml (1.7-8.6)FSH0.86 mIu/ml (0.7-11.1)Testosterone <20 ng/dl (118-949)1.97 ng/ml (2.49-8.37)<20 ng/dl (72-853)Prolactin24.78 ng/ml (4.04-15.2)229 (31-433)FBS87HB12.212.8Ferritin318200Vit D (25 OH)9.519

20. 201401.04.12FBS78BS 2h after 75g Glu121Insulin - Fasting12.7(2.6-24.9)Insulin - 2h after 75g Glu123.7IGF129.6(140.2-462.7)1401.04.12Chol188TG179LDL105HDL58AST32ALT34

21. Paraclinic evaluation Liver Sonography 1402.04.13:Mild hepatomegaly, Liver span: 162 mmFatty liver II-IIIOthers data: NlHypopituitary MRI 1400.12.14: Sella, Pituitary: NlHomogeneous both before & after contrast 21

22. Histiocytosis Hypothalamus involvement (DI – Polyphagia – Panhypopituitarism)Bone & dental involvement (Mastoid – Maxilla – Mandible)Panhypopituitarism 22

23. AGENDACase PresentationLangerhans cell histiocytosis Overview Endocrine involvement Why does our patient have a normal (even elevated) stature despite GH deficiency?Effect of obesity & various hormones on linear growthRole of insulin in growth / HOMA-IR When & why did our patient develop GH deficiency (Panhypopituitarism)?Management 23

24. AGENDA24

25. AGENDACase PresentationLangerhans cell histiocytosis Overview Endocrine involvement Why does our patient have a normal (even elevated) stature despite GH deficiency?Effect of obesity & various hormones on linear growthRole of insulin in growth / HOMA-IR When & why did our patient develop GH deficiency (Panhypopituitarism)?Management 25

26. Langerhans cell histiocytosis Overview Langerhans cell histiocytosis is a rare neoplasm of hematopoietic myeloid precursor cells that most commonly affects white male children, with a peak incidence of 1 to 3 years of age.Histiocytes (tissue macrophages) derive from hematopoietic myeloid progenitors, which further differentiate into monocytes, macrophages, and dendritic cells. Despite their phenotypic resemblance to normal Langerhans cells, which are dendritic cells of the skin and mucosa, the pathologic cells in Langerhans cell histiocytosis (LCH) derive from immature myeloid precursor cells. In the past, they had been erroneously thought to derive from Langerhans cells, because of their phenotypic resemblance and shared markers. 26(2018) Krooks J, Minkov M, Weatherall AG. Langerhans cell histiocytosis in children: History, classification, pathobiology, clinical manifestations, and prognosis. J Am Acad Dermatol. 2018 Jun;78(6):1035-1044. doi: 10.1016

27. Langerhans cell histiocytosis Overview The clinical presentation and subsequent course may vary remarkably, from single-system disease that may resolve spontaneously to treatment refractory multisystem involvement with a 20% mortality.Significant risk factors for LCH include:Maternal urinary tract infection during pregnancy, feeding problems or blood transfusions during infancy, Hispanic ethnicity, crowding, low education level, neonatal infections, solvent exposure, family history of thyroid disease and in vitro fertilization. Protective factors include black race, childhood vaccinations and supplemental vitamins. 27(2018) Krooks J, Minkov M, Weatherall AG. Langerhans cell histiocytosis in children: History, classification, pathobiology, clinical manifestations, and prognosis. J Am Acad Dermatol. 2018 Jun;78(6):1035-1044. doi: 10.1016

28. Langerhans cell histiocytosis Overview Sites of involvement include the bone (79%), skin (36%), pituitary gland (25%), liver (16%), bone marrow (15%), spleen (14%), lymph nodes (13%), lungs (13%), and central nervous system (5%)28(2019) Leung AKC, Lam JM, Leong KF. Childhood Langerhans cell histiocytosis: a disease with many faces. World J Pediatr. 2019 Dec;15(6):536-545. doi: 10.1007

29. Langerhans cell histiocytosis Overview Bone: The most common site of involvement is the skull, followed by the spine, extremities, pelvis, and ribs. The hands and feet are often spared. Skin:First manifestation in approximately 80% of cases and are often the leading clue for disease diagnosis. Common cutaneous manifestations include a seborrheic dermatitis-like eruption. 29(2019) Leung AKC, Lam JM, Leong KF. Childhood Langerhans cell histiocytosis: a disease with many faces. World J Pediatr. 2019 Dec;15(6):536-545. doi: 10.1007

30. Langerhans cell histiocytosis Overview Endocrine: Hypothalamic–pituitary axis: Central diabetes insipidus is the most common endocrine manifestation.Approximately 50% of patients with central diabetes insipidus develop deficiency of anterior pituitary hormones (such as GH, TSH, ACTH, LH, FSH) with resultant growth failure, hypothyroidism, hyperprolactinemia, hypoadrenalism, hypogonadism, amenorrhea, and precocious or delayed puberty. Non-endocrine hypothalamic dysfunction may present with eating disorders, obesity, sleeping disorders, fatigability, temperature instability, and autonomic disturbance. 30(2019) Leung AKC, Lam JM, Leong KF. Childhood Langerhans cell histiocytosis: a disease with many faces. World J Pediatr. 2019 Dec;15(6):536-545. doi: 10.1007

31. Langerhans cell histiocytosis Overview Endocrine: Hypothalamic–pituitary axis: Hormone deficiencies develop in 20% of patients overall. The second most common endocrinopathy is growth hormone deficiency (10%). Accordingly, growth should be monitored in all LCH patients, particularly in those with diabetes insipidus, who have a 37% and 53% 5- and 10-year risk, respectively, of developing growth hormone deficiency. Thyroid involvement is rare, with only 75 cases reported in the literature, and may present with either diffuse (59%) or nodular (26%) nontender enlargement. Patients are typically euthyroid (41%), hypothyroid (20%), or subclinically hypothyroid (11%) 31(2018) Krooks J, Minkov M, Weatherall AG. Langerhans cell histiocytosis in children: History, classification, pathobiology, clinical manifestations, and prognosis. J Am Acad Dermatol. 2018 Jun;78(6):1035-1044. doi: 10.1016

32. Langerhans cell histiocytosis Overview Liver and spleen Bone marrow Lymph nodes Lungs Central nervous system Historically, different clinical phenotypes of LCH have been described as distinct entities (e.g, eosinophilic granuloma of bone, Hand-Schüller-Christian disease, Letterere-Siwe disease, and Hashimotoe-Pritzker disease). 321: (2019) Leung AKC, Lam JM, Leong KF. Childhood Langerhans cell histiocytosis: a disease with many faces. World J Pediatr. 2019 Dec;15(6):536-545. doi: 10.10072:(2018) Krooks J, Minkov M, Weatherall AG. Langerhans cell histiocytosis in children: History, classification, pathobiology, clinical manifestations, and prognosis. J Am Acad Dermatol. 2018 Jun;78(6):1035-1044. doi: 10.1016

33. Langerhans cell histiocytosis Overview Management Treatment depends on the site and extent of the disease.The current recommended first-line therapy for patients with multisystem LCH is 12 months therapy with prednisone and vinblastine. Vemurafenib, a BRAF V6000 inhibitor, may be considered for the subset of high-risk patients with same mutations. Additional therapy: Complications such as diabetes insipidus, short stature, hypothyroidism, hypoadrenalism, and hypogonadism may require treatment with appropriate hormones. Hearing loss and musculoskeletal disabilities should be properly treated. Patients with LCH need to have long-term follow-up to monitor for disease recurrence and late effects. 33(2019) Leung AKC, Lam JM, Leong KF. Childhood Langerhans cell histiocytosis: a disease with many faces. World J Pediatr. 2019 Dec;15(6):536-545. doi: 10.1007

34. Langerhans cell histiocytosis Overview The hypothalamicpituitary system is involved in up to 50% of children with LCH who prevalently develop DI.Hypothalamic involvement in these patients may also cause sleep disturbances, hyperphagia with obesity, temperature dysregulation & behavioral abnormalities. Anterior pituitary dysfunction occurs in up to 20% of patients. Growth retardation is found in 40% of patients with prepubertal onset of disease and is caused by GH deficiency which is the most frequent and earlier anterior pituitary hormone abnormality due to altered formation and/or release of GHRH by the hypothalamus.Gonadotrophin deficiency is also common, Mild hyperprolactinemia may be observed in adult LCH patients.34(2017) Shlomo Melmed, The Pituitary, 4th Edition P: 320

35. AGENDACase PresentationLangerhans cell histiocytosis Overview Endocrine involvement Why does our patient have a normal (even elevated) stature despite GH deficiency?Effect of obesity & various hormones on linear growthRole of insulin in growth / HOMA-IR When & why did our patient develop GH deficiency (Panhypopituitarism)?Management 35

36. Why does our patient have a normal (even elevated) stature despite GH deficiency?Also, What is cause of his feet & hands bigness?This is a rare & extra-natural condition, and these are so poor documentations to can say which hormones could lead growth in this situation. 36

37. 37(2016) De Groot J, Larry Jameson MD PhD Leslie J, Endocrinology Adult & Pediatric 7th Edition P: 2669For our patient:IGF1: 29.6

38. Why does our patient have a normal (even elevated) stature despite GH deficiency?Case reportsIn summary, we have reported an unusual case of GH deficiency (23 y-male) in which the patient attained normal height with unfused epiphyses because of hypogonadotropic hypogonadism. This case suggests that males can grow without GH under certain circumstances. ¹37 y-male + Growth independent of GH has been reported in some cases of craniopharyngioma, but in only one case of hypopituitarism. ²There exist some growth promoting factors other than GH and IGF-I. Thyroid hormone, insulin, prolactin (PRL) and IGF-II play significant roles in postnatal somatic growth even without GH. ²381: (2000) Wada S, et al. A patient of hypogonadotropic hypogonadism accompanied by growth hormone deficiency and decreased bone mineral density who attained normal growth. Intern Med. 2000 Aug;39(8):641-5. doi: 10.21692: (1998) Kageyama K, Watanobe H, Nasushita R, Nishie M, Horiba N, Suda T. A hypopituitary patient who attained tall stature without growth hormone. Intern Med. 1998 May;37(5):472-5. doi: 10.2169

39. Why does our patient have a normal (even elevated) stature despite GH deficiency?GH-deficient newborns can have a length within the normal range, which suggests that other growth factors dominate longitudinal gain during gestation.Obese children grow at a normal rate despite their low serum GH levels.Several possible mechanisms might underlie the growth stimulation in obese children, such as:Elevated levels of insulin Reduced levels of IGF binding protein-1Elevated leptin levels in obese children were found to affect the bone growthSex hormones stimulate growth through a direct GH-independent effect on the bone growth centers39(2002) Phillip M, et all. Growth without growth hormone. J Pediatr Endocrinol Metab. 2002 Dec;15 Suppl 5:1267-72

40. Why does our patient have a normal (even elevated) stature despite GH deficiency?Growth patterns of obesity during childhood are well described, documenting increased linear growth in early childhood associated with accelerated pubertal maturation resulting in normal adult height. Decreased baseline GH levels have been well documented in obese patients. In prepubertal children with simple obesity, growth velocity is increased in association with these lower GH values. 40(2013) Fennoy I. Effect of obesity on linear growth. Curr Opin Endocrinol Diabetes Obes. 2013 Feb;20(1):44-9. doi: 10.1097/MED.0b013e32835b7f15

41. Why does our patient have a normal (even elevated) stature despite GH deficiency?Ghrelin has been considered a potential regulator of GH release in obesity. Administration of ghrelin to humans and rats results in increased GH secretion as well as stimulating appetite.Ghrelin is also known to stimulate insulin secretion. Ghrelin levels in obese children are lower than in normal.The contribution of ghrelin stimulation of insulin to the growth patterns in childhood obesity, however, remains to be determined. 41(2013) Fennoy I. Effect of obesity on linear growth. Curr Opin Endocrinol Diabetes Obes. 2013 Feb;20(1):44-9. doi: 10.1097/MED.0b013e32835b7f15

42. Why does our patient have a normal (even elevated) stature despite GH deficiency?In obesity, despite low GH values, total IGF-1 has been measured as low to slightly reduced or normal leading to the hypothesis that free IGF-1 is elevated.However, free IGF-1 has been variously reported as low or elevated.Diet has been implicated as a regulator of IGF levels. Short-term overeating itself was associated with suppressed GH, but maintenance of normal IGF-1, increased IGF-BP3, and increased free IGF-1 was thought to be related to decreased IGF-BP2.42(2013) Fennoy I. Effect of obesity on linear growth. Curr Opin Endocrinol Diabetes Obes. 2013 Feb;20(1):44-9. doi: 10.1097/MED.0b013e32835b7f15

43. Why does our patient have a normal (even elevated) stature despite GH deficiency?Insulin has also been shown to negatively feed back on the pituitary to inhibit GH release in normal weight individuals and in the obese.Increased insulin secretion in SGA infants was associated with both the catch-up growth and increased linear growth.Insulin, as a growth promoting hormone however, may also contribute to the increased linear growth of simple obesity. 43(2013) Fennoy I. Effect of obesity on linear growth. Curr Opin Endocrinol Diabetes Obes. 2013 Feb;20(1):44-9. doi: 10.1097/MED.0b013e32835b7f15

44. Why does our patient have a normal (even elevated) stature despite GH deficiency?Leptin Leptin receptors have been identified in the hypothalamus and in the gonadotrope cells of the anterior pituitary. In the hypothalamus, leptin has a direct stimulatory effect on the HPG axis by accelerating GnRHsecretion. ¹AdiponectinResistin 44(2003) Shalitin S, Phillip M. Role of obesity and leptin in the pubertal process and pubertal growth--a review. Int J Obes Relat Metab Disord. 2003 Aug;27(8):869-74. doi: 10.1038

45. Why does our patient have a normal (even elevated) stature despite GH deficiency?Some features of IR in children discussed herein are: a strong tendency to low birth weight for gestational age, adverse effects of adrenarche and therapeutic steroid therapy, predisposition to premature pubarche,acanthosis nigricans, tall stature despite pituitary GH suppression, allergic diathesis, hyperandrogenism and PCOS, dyslipidemia and fatty liver disease. Children with IR are often taller than their peers and outgrow their parents. A small number even shown acromegaloid features despite suppressed pituitary GH levels. 45(2007) Maclaren NK, et al. Childhood obesity and insulin resistance. Cell Biochem Biophys. 2007;48(2-3):73-8. doi: 10.1007/s12013-007-0017-6

46. 46(2018) David G. Gardner, et al. Greenspan’s Basic and Clinical Endocrinology 10th Edition P: 155 Why does our patient have a normal (even elevated) stature despite GH deficiency?

47. Insulin resistance & Acromegaloid feature Insulin and IGF-I share a range of biological activities.Insulin and IGF-I both exhibit affinity for each other’s primary receptors. ¹Activation intact mitogenic signaling pathways and stimulation pathological tissue growth induced by the extreme elevation of serum insulin occurring in compensation for the impaired metabolic signaling. ²471: (2011) Sam AH, Tan T, Meeran K. Insulin-mediated "pseudoacromegaly". Hormones (Athens). 2011 Apr-Jun;10(2): 156-61. doi: 10.143102: (2019) Moradi L, Amiri F, Shahbazian H. Insulin resistance and pseudoacromegaly: A case report. Diabetes Metab Syndr. 2019 Mar-Apr;13(2):901-903. doi: 10.1016

48. Insulin resistance & Acromegaloid feature The human proinsulin polypeptide begins with the 30-amino-acid B chain domain, extends through a 35-amino-acid connecting segment & ends with the 21–amino-acid A chain domain.Mature IGF-1 and IGF-2 contain 70 and 67 amino acids & the regions homologous tothe B chain of insulin, the C peptide, the A chain and also a D extension peptide. Proinsulin has a longer C peptide region compared to IGF-1 or IGF-2. The A chain and B chain peptide regions are of similar length. The sequences in this region are 41% and 43% homologous with proinsulin. 48(2016) De Groot J, Larry Jameson MD PhD Leslie J, Endocrinology Adult & Pediatric 7th Edition P: 258,361

49. Insulin resistance & Acromegaloid feature The receptors are heterotetrameric glycoprotein composed of two ligand-binding subunits termed alpha subunits and two beta subunits.The IGF-1 receptor binds IGF-1IGF-2 binds with sixfold lower affinity,and insulin with a 200- to 300-fold lower affinity. α-subunit of both the IGF-1 and insulin receptors shows that there are two important differences, one in LR1 and one in CR1.49(2016) De Groot J, Larry Jameson MD PhD Leslie J, Endocrinology Adult & Pediatric 7th Edition P: 362,363

50. Insulin resistance & Acromegaloid feature 50(2016) De Groot J, Larry Jameson MD PhD Leslie J, Endocrinology Adult & Pediatric 7th Edition P: 560

51. Why does our patient have a normal (even elevated) stature despite GH deficiency?Does our patient have insulin resistance? 511401.04.12FBS78BS 2h after 75g Glu121Insulin - Fasting12.7(2.6-24.9)Insulin - 2h after 75g Glu123.7IGF129.6(140.2-462.7)

52. Why does our patient have a normal (even elevated) stature despite GH deficiency?52(2016) De Groot J, Larry Jameson MD PhD Leslie J, Endocrinology Adult & Pediatric 7th Edition P: 2682For our patient: 78 12.7 121 123.7

53. Why does our patient have a normal (even elevated) stature despite GH deficiency? Normal Insulin levels & HOMA-IRA mathematical model HOMA-IR = (insulin * glucose) / 22.5for the glucose concentration in mmol/L, or HOMA-IR: 2.45 HOMA-IR = (insulin * glucose) / 405for glycemia in mg/dL. In both cases the insulin is in mU/L53(1985) Matthews DR, et al. Homeostasis model assessment: insulin resistance and beta-cell function from fasting plasma glucose and insulin concentrations in man. Diabetologia. 1985 Jul;28(7):412-9. doi: 10.1007/BF00280883

54. Why does our patient have a normal (even elevated) stature despite GH deficiency? Normal Insulin levels & HOMA-IR The HOMA-IR cut-off points to diagnose insulin resistance cannot be readily applied to all populations and may vary from race to race.Youden index [sensitivity- (1-specificity)], and the point with shortest distance value form the point (0,1) [(1 - sensitivity)² + (1 - specificity)²] were calculated. The HOMA-IR method requires measuring a single fasting plasma glucose and the corresponding fasting plasma insulin level 54(2007) Esteghamati A, et al. Optimal cut-off of homeostasis model assessment of insulin resistance (HOMA-IR) for the diagnosis of metabolic syndrome: third national surveillance of risk factors of non-communicable diseases in Iran (SuRFNCD-2007). Nutr Metab (Lond). 2010 Apr 7;7:26. doi: 10.1186/1743-7075-7-26

55. 55(2007) Esteghamati A, et al. Optimal cut-off of homeostasis model assessment of insulin resistance (HOMA-IR) for the diagnosis of metabolic syndrome: third national surveillance of risk factors of non-communicable diseases in Iran (SuRFNCD-2007). Nutr Metab (Lond). 2010 Apr 7;7:26. doi: 10.1186/1743-7075-7-26

56. Why does our patient have a normal (even elevated) stature despite GH deficiency? Normal Insulin levels & HOMA-IR The optimal cut-off point of HOMA-IR for the diagnosis of MetS in our population was estimated to be 1.775 in non-diabetics and around 4 in diabetic patients. For our patent: HOMA-IR: 2.45 In line with previous population-based studies, we found that insulin resistance and MetS were significantly associated, and HOMA-IR levels were directly related to the number of MetS components. 56(2007) Esteghamati A, et al. Optimal cut-off of homeostasis model assessment of insulin resistance (HOMA-IR) for the diagnosis of metabolic syndrome: third national surveillance of risk factors of non-communicable diseases in Iran (SuRFNCD-2007). Nutr Metab (Lond). 2010 Apr 7;7:26. doi: 10.1186/1743-7075-7-26

57. Why does our patient have a normal (even elevated) stature despite GH deficiency?Children with hyperinsulinemia have an accelerated growth. While it was initially assumed that the growth activities of insulin are facilitated via cross-talk with the closely related insulin-like growth factor-1 receptor (IGF-1R), it is now clear that the vast majority of these activities are mediated via direct interaction with the insulin receptor (IR).57(2008) Laron Z. Insulin--a growth hormone. Arch Physiol Biochem. 2008 Feb;114(1):11-6. doi: 10.1080(2020) Laron Z, Werner H. Insulin: A Growth Hormone and Potential Oncogene. Pediatr Endocrinol Rev. 2020 Mar;17(Suppl 1):191-197. doi: 10.17458

58. Why does our patient have a normal (even elevated) stature despite GH deficiency?Serum insulin levels are poor measures of insulin resistance. Furthermore, there is no clinical benefit in measuring insulin resistance in clinical practice. Clinicians should shift from identifying "insulin resistance" to identifying risk factors, such as fasting glucose and lipid levels, hypertension and central obesity. These proven risk factors converge within the metabolic syndrome. Individuals "at risk" of diabetes and atherosclerotic cardiac disease can be identified simply and inexpensively.58(2006) Samaras K, et al. Insulin levels in insulin resistance: phantom of the metabolic opera? Med J Aust. 2006 Aug 7;185(3):159-61. doi: 10.5694

59. AGENDACase PresentationLangerhans cell histiocytosis Overview Endocrine involvement Why does our patient have a normal (even elevated) stature despite GH deficiency?Effect of obesity & various hormones on linear growthRole of insulin in growth / HOMA-IR When & why did our patient develop GH deficiency (Panhypopituitarism)?Management 59

60. When & why did our patient develop GH deficiency (Panhypopituitarism)?Heritable Disorders Acquired Disorders 60(2020) Williams Textbook of Endocrinology, 14th edition P:1585

61. When & why did our patient develop GH deficiency (Panhypopituitarism)?Our patient stature was documented near normal until age 2 y old.He has been observed by oncologist until about 7 years, and seems all thing good on that time.His stature during school times, seems be good and about mid range of Nl. Father reported a period of polyphagia about age 4-5 y, that may be a feature of hypothalamus involvement, so it may be considered as an option for beginning time of panhypopituitarism. >>> ??? 61

62. When & why did our patient develop GH deficiency (Panhypopituitarism)?There is not any significant document about adverse effect of Vinblastine, drug of choice for LCH, on pituitary causing hormone deficiency. (can cause SIADH) Effect of chemotherapy & radiotherapy during pregnancy on fetus The use of cytotoxic drugs during fertilization or implantation can lead to one of 2 opposite phenomena: the death of the embryo or the proper development of the embryo. The administration of cytotoxic drugs during the 1st trimester is particularly dangerous because it is frequently associated with the development of malformations, embryo death, and spontaneous abortion. Transient myelosuppression / Neuropsychological issues / Heart development. ¹ 621: (2016) Esposito S, Tenconi R, Preti V, Groppali E, Principi N. Chemotherapy against cancer during pregnancy: A systematic review on neonatal outcomes. Medicine (Baltimore). 2016 Sep;95(38):e4899. doi: 10.1097

63. When & why did our patient develop GH deficiency (Panhypopituitarism)?LCH on childhood by DI & bone envovlement manifestation >>> Delayed hormone deficiency, At time: Prepubertal that has allowed to patient for normal growth.Polyphagia at age 4-5 & consequent Obesity may have played a role by insulin resistance effect, and may have contributed in Growth development despite GH deficiency. 63

64. AGENDACase PresentationLangerhans cell histiocytosis Overview Endocrine involvement Why does our patient have a normal (even elevated) stature despite GH deficiency?Effect of obesity & various hormones on linear growthRole of insulin in growth / HOMA-IR When & why did our patient develop GH deficiency (Panhypopituitarism)?Management 64

65. ManagementHormone replacement therapy with an architectural structure mimicing natural puberty.Management of Cosmetic AppearanceOrthopedic surgery 65

66. Thanks for your attention66